The invention provides cyclohexylamine derivatives as N-Methyl-D-Aspartate (NMDA) antagonists, pharmacological compositions comprising the derivatives, and methods of treating diseases and disorders responsive to antagonism of NMDA receptors using the derivatives.
Many of the physiological and pathophysiological effects of the endogenous excitatory neurotransmitter glutamate are mediated via actions at N-Methyl-D-Asparate (NMDA) receptors. Over-excitation of the NMDA receptors on postsynaptic cellsxe2x80x94mediated by excessive release of glutamate from nerve endings or glial cellsxe2x80x94results in a massive calcium ion influx through a calcium ion channel into neuronal cells, leading to neuronal cell death. These events occur under ischemic or hypoxic conditions such as, for example, stroke, hypoglycemia, cardiac arrest, or acute physical trauma.
NMDA receptors in vivo form an NMDA receptor channel complex in cell walls comprising at least three binding domains, including a glutamic acid (or NMDA) recognition site, a channel blocking binding site, and a strychnine-insensitive glycine binding site. Physiologically, a blockade of at least one of these sites terminates the channel opening of the NMDA receptor, thereby preventing calcium ion influx into cells. Accordingly, an NMDA receptor antagonist is therapeutically useful because it minimizes damage to the central nervous system induced by calcium ion influx under ischemic or hypoxic conditions.
A functional NMDA receptor is comprised of the combination of at least one subunit termed xe2x80x9cNR1,xe2x80x9d which has 8 splice variants including NR1A, and one (or more) subunit termed xe2x80x9cNR2A,xe2x80x9d xe2x80x9cNR2B,xe2x80x9d xe2x80x9cNR2C,xe2x80x9d and xe2x80x9cNR2D.xe2x80x9d The combinations are designated NR1/2A, NR1/2B, NR1/2C and NR1/2D, respectively. The different NR2 subunits have distinct developmental and anatomical distributions. This suggests that agents that selectively antagonize one NR1/NR2 combination would have therapeutic actions without the psychotomimetic or dysphoric side effects associated with antagonists which block multiple NR1/NR2 combinations.
A subtype-selective NMDA receptor antagonist may be identified by methods well-known in the pharmaceutical arts, such as, for example, screening compounds in an electrophysiology assay. In one such electrophysiology assay, different subunit combinations of recombinant NR1 and NR2 receptors are expressed in Xenopus oocytes, and a potential agent is administered at different concentrations. NMDA-based electrical currents are activated by co-administration of fixed concentrations of an excitatory amino acid such as, for example, glutamic acid or glycine. The ability of an agent to antagonize the activation of the electrical current by an excitatory amino acid is measured by recording the change in the current versus the change in the concentration of the agent.
Screening of compounds in recent years have identified a number of NMDA receptor antagonists that have been used in animal and clinical human studies to demonstrate proof of concept for use of such an antagonist in the treatment of a variety of disorders. Disorders known to be responsive to blockade of NMDA receptors include acute cerebral ischemia (stroke or cerebral trauma, for example), muscular spasm, convulsive disorders, pain, including chronic and neuropathic pain, anxiety, and chronic neurodegenerative disorders such as Parkinson""s disease. NMDA receptor antagonists may also be used to prevent tolerance to opiate analgesia or to help control symptoms of withdrawal from addictive drugs. In fact, excessive excitation by neurotransmitters may be responsible for the loss of neurons in a wide variety of conditions. Additional conditions include cerebral vascular disorders such as cerebral ischemia or cerebral infarction resulting in a range of conditions such as thromboembolic or hemorrhagic stroke, cerebral vasospasm, hypoglycemia, cardiac arrest, status epilepticus, perinatal, asphyxia anoxia, such as from near drowning, pulmonary surgery and cerebral trauma, as well as lathyrism, Alzheimer""s disease, and Huntington""s disease. Other conditions amendable to treatment with an subtype-selective NMDA receptor antagonist include amyotrophic lateral sclerosis (ALS), epilepsy, and schizophrenia.
For example, studies have demonstrated that compounds that act as antagonists at NMDA receptors have beneficial pharmacological effects on patients suffering from Parkinson""s disease. In Parkinson""s disease, there is a loss of dopamine neurons in the substantia nigra. Secondary to this dopamine loss is a hyperactivity of specific brain glutamatergic pathways. This glutamatergic hyperactivity is thought to mediate some of the pathophysiological aspects of Parkinson""s disease, as well as some of the side effects associated with the long-term treatment of the disease by dopamine agonists, such as L-DOPA, pergolide, ropinirole, or pramipexole. Clinical studies in humans have demonstrated that antagonists at NMDA receptors have beneficial effects in Parkinson""s disease or in treating the side effects associated with the treatment of Parkinson""s disease with dopamine agonists.
Pain is another example of a condition shown to be responsive to NMDA receptor antagonism. For example in previous studies, stimulation of NMDA receptors by afferent nerves transmitting painful stimuli has been demonstrated to be involved in hyperalgesic and neuropathic pain states. Animal studies have demonstrated that compounds that act as antagonists at NMDA receptors have beneficial effects in treating hyperalgesic and neuropathic pain states.
However, while NMDA antagonists have been successfully used to demonstrate the proof of concept mentioned above, very few, if any, of these antagonists have shown a suitable drug profile in clinical studies. This is so even though numerous NMDA receptor antagonists have been synthesized and tested.
The difficulty referenced above with demonstrating clinical utility of NMDA receptor antagonists has been the antagonists"" lack of NMDA receptor subtype selectivity and/or biological activity when dosed orally. Before the present invention, many of the drugs of the NMDA receptor antagonist class were nonselective antagonists of NMDA receptor subtypes that were administered intravenously (IV), which accounts for their undesired side effects and the present need for selective, orally efficacious agents, respectively. Given that the need for medicinal agents that treat diseases responsive to antagonism of NMDA receptors remains unmet, the search for NMDA receptor antagonists that are subtype-selective and orally efficacious continues.
We have discovered a series of novel cyclohexylamines that are subtype-selective NMDA receptor antagonists and are efficacious in vivo when dosed orally. All that is needed to practice the invention is to administer from 1 to 6 times daily to a patient in need thereof, a therapeutically effective amount of a compound of the invention. As is discussed below, determination of dosage forms and amounts of the invention compounds, routes of administration, and identification of patients in need of treatment, is within the average skill in the pharmaceutical and medical arts.
One embodiment of the present invention is a compound of Formula I 
and pharmaceutically acceptable salts thereof, wherein:
* means cis or trans or mixtures thereof;
G and H are 
xe2x80x83but are never the same;
R is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, C(O)R2, C(O)OR2, C(O)NHR2, aralkyl, hydroxyalkyl, aminoalkyl, amino (hydroxy) alkyl, alkylaminoalkyl, carboxyalkyl, or OR2 wherein R2 is alkyl alkenyl or aralkyl;
R1 is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkylaminoalkyl, hydroxyalkyl, (aminocarbonyl)-alkyl, (alkylthio)-alkyl, carboxyalkyl, haloalkyl, and halogen;
g is an integer of from 0 to 3;
V is (CH2)n or (CH2)mxe2x80x94Cxe2x95x90O, wherein n is an integer of from 1 to 4, and m is an integer of from 0 to 4;
X1 is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, aralkyl, substituted aralkyl, halogen, haloalkyl, cyano, nitro, amino, aminoalkyl, alkylaminoalkyl, hydroxyalkyl, carboxyalkyl, (aminocarbonyl)-alkyl, (alkylthio)-alkyl, or C(O)-alkyl;
d is an integer of from 0 to 2;
E is hydrogen; and
Y is OH; or
E and Y may be taken together with the phenylene to which they are attached to form a fused 9- or 10-membered bicyclic ring, containing from 0 to 3 heteroatoms in Exe2x80x94Y selected from N, O, and S, wherein E is a linker group containing 2 or 3 atoms of the bicyclic ring, and Y is a hydrogen bond donor group containing 1 atom of the bicyclic ring; and
B is a 4-, 5-, or 6-membered, carbon-linked heterocyclene, containing from 1 to 3 heteroatoms, which are N, O, or S, selected from the group consisting of:
(i) 1-aza-2-cyclobutanon-3,4-diyl of formula 
(ii) a 5-membered aromatic, nonaromatic dihydro, or nonaromatic tetrahydro diradical heterocyclic ring having carbon atoms and from 1 to 3 heteroatoms selected from N, O, and S;
(iii) a 5-membered oxo-substituted, nonaromatic tetrahydro, diradical heterocyclic ring having carbon atoms and 1 or 2 heteroatoms selected from N, O, and S;
(iv) a 6-membered aromatic, nonaromatic tetrahydro, or nonaromatic hexahydro diradical heterocyclic ring having carbon atoms and 1 or 2 heteroatoms, which heteroatoms are nitrogen, and
(v) a 6-membered nonaromatic oxo-substituted hexahydro diradical heterocyclic ring having carbon atoms and 1 or 2 heteroatoms which are nitrogen and 0 or 1 heteroatom which is oxygen
xe2x80x83wherein the atoms of the heterocyclene ring that are bonded to the group V and the phenyl bearing the group (X1)d are carbon atoms, and further wherein when B is a nonaromatic heterocycle containing sulfur, said sulfur may further comprise 
Preferred are compounds of Formula II 
and pharmaceutically acceptable salts thereof wherein *, R1, g, R, X1, and d are as defined above for Formula I;
B is a heterocyclene selected from the group consisting of: 
wherein X is O, S, or Nxe2x80x94R3 wherein R3 is hydrogen or alkyl;
E and Y are taken together with the phenylene to which they are attached to form a fused 9- or 10-membered bicyclic ring, containing from 0 to 3 heteroatoms in Exe2x80x94Y selected from N, O, and S, wherein E is a linker group containing 2 or 3 atoms of the bicyclic ring, and Y is a hydrogen bond donor group containing 1 atom of the bicyclic ring;
V is CH2; and
one X1 is ortho to B and para to E.
More preferred are compounds of Formula II and pharmaceutically acceptable salts thereof wherein
Y is selected from xe2x80x94N(H)xe2x80x94, xe2x80x94CH(OH)xe2x80x94, and xe2x80x94N(OH)xe2x80x94, and
E is selected from xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90Nxe2x80x94, xe2x80x94C(O)xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94C(O)xe2x80x94, xe2x80x94CH2xe2x80x94S(O)xe2x80x94, xe2x80x94CH2xe2x80x94S(O)2xe2x80x94, xe2x80x94Nxe2x95x90C(H)xe2x80x94, xe2x80x94N(H)xe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94Sxe2x80x94C(O)xe2x80x94, xe2x80x94Nxe2x95x90Nxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94C(H)xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94C(O)xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94S(O)xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94S(O)2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94C(O)xe2x80x94, xe2x80x94Nxe2x95x90CHxe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94C(O)xe2x80x94, xe2x80x94Sxe2x80x94CH2xe2x80x94C(O)xe2x80x94, and xe2x80x94N(H)xe2x80x94C(O)xe2x80x94C(O)xe2x80x94; or
Y is selected from xe2x95x90C(OH)xe2x80x94; and
E is selected from xe2x80x94CHxe2x95x90CHxe2x80x94C(H)xe2x95x90, xe2x80x94C(O)xe2x80x94C(H)xe2x95x90, xe2x80x94C(O)xe2x80x94Nxe2x95x90, xe2x80x94Oxe2x80x94Nxe2x95x90, xe2x80x94Sxe2x80x94Nxe2x95x90, xe2x80x94C(O)xe2x80x94N(H)xe2x80x94Nxe2x95x90, xe2x80x94CHxe2x95x90Nxe2x80x94Nxe2x95x90, xe2x80x94CHxe2x95x90N(O)xe2x80x94Nxe2x95x90, and xe2x80x94N(H)xe2x80x94C(O)xe2x80x94Nxe2x95x90.
Still more preferred are compounds of Formula II and pharmaceutically acceptable salts thereof wherein
xe2x80x94Exe2x80x94Yxe2x80x94 is selected from the group consisting of
xe2x80x94CHxe2x95x90CHxe2x80x94N(H)xe2x80x94,
xe2x80x94(CH2)2xe2x80x94N(H)xe2x80x94,
xe2x80x94CHxe2x95x90Nxe2x80x94N(H)xe2x80x94,
xe2x80x94C(O)xe2x80x94CH2xe2x80x94N(H)xe2x80x94,
xe2x80x94CH2xe2x80x94C(O)xe2x80x94N(H)xe2x80x94,
xe2x80x94CH2xe2x80x94S(O)xe2x80x94N(H)xe2x80x94,
xe2x80x94CH2xe2x80x94S(O)2xe2x80x94N(H)xe2x80x94,
xe2x80x94CHxe2x95x90CHxe2x80x94CH(OH)xe2x80x94,
xe2x80x94(CH2)2xe2x80x94CH(OH)xe2x80x94,
xe2x80x94C(O)xe2x80x94C(H)xe2x95x90C(OH)xe2x80x94,
xe2x80x94C(O)xe2x80x94Nxe2x95x90C(OH)xe2x80x94,
xe2x80x94Nxe2x95x90CHxe2x80x94N(H)xe2x80x94,
xe2x80x94N(H)xe2x80x94C(O)xe2x80x94N(H)xe2x80x94,
xe2x80x94Oxe2x80x94C(O)xe2x80x94NHxe2x80x94,
xe2x80x94Sxe2x80x94C(O)xe2x80x94NHxe2x80x94,
xe2x80x94Oxe2x80x94Nxe2x95x90CH(OH)xe2x80x94,
xe2x80x94Sxe2x80x94Nxe2x95x90CH(OH)xe2x80x94,
xe2x80x94Nxe2x95x90Nxe2x80x94N(H)xe2x80x94,
xe2x80x94Nxe2x95x90Nxe2x80x94N(OH)xe2x80x94,
xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90C(OH)xe2x80x94,
xe2x80x94(CH2)3xe2x80x94CH(OH)xe2x80x94,
xe2x80x94(CH2)2xe2x80x94C(O)xe2x80x94N(H)xe2x80x94,
xe2x80x94(CH2)2xe2x80x94S(O)xe2x80x94N(H)xe2x80x94,
xe2x80x94(CH2)2xe2x80x94S(O)2xe2x80x94N(H)xe2x80x94,
xe2x80x94CHxe2x95x90CHxe2x80x94C(O)xe2x80x94N(H)xe2x80x94,
xe2x80x94C(O)xe2x80x94NHxe2x80x94Nxe2x95x90C(OH)xe2x80x94,
xe2x80x94CHxe2x95x90Nxe2x80x94Nxe2x95x90C(OH)xe2x80x94,
xe2x80x94CHxe2x95x90N(O)xe2x80x94Nxe2x95x90C(OH)xe2x80x94,
xe2x80x94N(H)xe2x80x94C(O)xe2x80x94Nxe2x95x90C(OH)xe2x80x94,
xe2x80x94Nxe2x95x90CHxe2x80x94C(O)xe2x80x94NHxe2x80x94,
xe2x80x94Oxe2x80x94CH2xe2x80x94C(O)xe2x80x94NHxe2x80x94,
xe2x80x94Sxe2x80x94CH2xe2x80x94C(O)xe2x80x94NHxe2x80x94, and
xe2x80x94N(H)xe2x80x94C(O)xe2x80x94C(O)xe2x80x94N(H)xe2x80x94.
Also preferred are compounds of Formula III 
and pharmaceutically acceptable salts thereof, wherein *, R1, g, R, X1, d, and V are as defined above for Formula I, and X is O, S, or Nxe2x80x94R3 wherein R3 is hydrogen or alkyl.
More preferred is a compound of Formula III and a pharmaceutically acceptable salt thereof, which is trans-6-(5-{[methyl-4-phenyl-cyclohexyl)-amino]-methyl-4,5-dihydro-isoxazol-3-yl}-3H-benzoxazol-2-one.
Also preferred are compounds of Formula IV 
and pharmaceutically acceptable salts thereof, wherein *, R1, g, R, X1, d, and V are as defined above for Formula I, and X is O, S, or Nxe2x80x94R3 wherein R3 is hydrogen or alkyl.
More preferred is a compound of Formula IV and pharmaceutically acceptable salts thereof, selected from the group consisting of:
trans-6-{5-[4-(4-fluoro-phenyl)-cyclohexylamino]methyl-2-oxo-oxazolidin-3-yl}-3H-benzoxazol-2-one;
trans-6-{5-[4-(4-fluoro-phenyl)-cyclohexylamino]methyl-2-oxo-oxazolidin-3-yl}-3H-benzoxazol-2-one hydrochloride;
trans-6-(5-{[4-(4-fluoro-phenyl)-cyclohexyll-methyl-amino}methyl-2-oxo-oxazolidin-3-yl)-3H-benzoxazol-2-one; and
trans-6-(5-{[4-(4-fluoro-phenyl)-cyclohexyll-methyl-amino}methyl-2-oxo-oxazolidin-3-yl)-3H-benzoxazol-2-one hydrochloride.
Also preferred are compounds of Formula V 
and pharmaceutically acceptable salts thereof, wherein *, R1, g, R, V, B, X1, and d are as defined above for Formula I.
Another embodiment of the present invention is a compound of Formulae VI and VIa 
and pharmaceutically acceptable salts thereof, wherein
* means cis or trans or mixtures thereof;
R is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, C(O)R2, C(O)OR2, C(O)NHR2, aralkyl, hydroxyalkyl, aminoalkyl, amino (hydroxy) alkyl, alkylaminoalkyl, carboxyalkyl, or OR2 wherein R2 is alkyl, alkenyl or aralkyl;
R1 is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkylaminoalkyl, hydroxyalkyl, (aminocarbonyl)-alkyl, (alkylthio)-alkyl, carboxyalkyl, haloalkyl, and halogen;
g is an integer of from 0 to 3;
V is (CH2)n or (CH2)mxe2x80x94Cxe2x95x90O, wherein n is an integer of from 1 to 4, and m is an integer of from 0 to 4;
X1 is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, aralkyl, substituted aralkyl, halogen, haloalkyl, cyano, nitro, amino, aminoalkyl, alkylaminoalkyl, hydroxyalkyl, carboxyalkyl, (aminocarbonyl)-alkyl, (alkylthio)-alkyl, or C(O)-alkyl;
d is an integer of from 0 to 2;
E is hydrogen; and
Y is OH; or
E and Y may be taken together with the phenylene to which they are attached to form a fused 9- or 10-membered bicyclic ring, containing from 0 to 3 heteroatoms in Exe2x80x94Y selected from N, O, and S, wherein E is a linker group containing 2 or 3 atoms of the bicyclic ring, and Y is a hydrogen bond donor group containing 1 atom of the bicyclic ring; and
B is a 4-, 5-, or 6-membered, carbon-linked heterocyclene, containing from 1 to 3 heteroatoms, which are N, O, or S, selected from the group consisting of:
(i) 1-aza-2-cyclobutanon-3,4-diyl of formula 
(ii) a 5-membered aromatic, nonaromatic dihydro, or nonaromatic tetrahydro diradical heterocyclic ring having carbon atoms and from 1 to 3 heteroatoms selected from N, O, and S;
(iii) a 5-membered oxo-substituted, nonaromatic tetrahydro, diradical heterocyclic ring having carbon atoms and 1 or 2 heteroatoms selected from N, O, and S;
(iv) a 6-membered aromatic, nonaromatic tetrahydro, or nonaromatic hexahydro diradical heterocyclic ring having carbon atoms and 1 or 2 heteroatoms, which heteroatoms are nitrogen, and
(v) a 6-membered nonaromatic oxo-substituted hexahydro diradical heterocyclic ring having carbon atoms and 1 or 2 heteroatoms which are nitrogen and 0 or 1 heteroatom which is oxygen
xe2x80x83wherein the atoms of the heterocyclene ring that are bonded to the group V and the phenyl bearing the group (X1)d are carbon atoms, and further wherein when B is a nonaromatic heterocycle containing sulfur, said sulfur may further comprise 
Preferred are compounds of Formula VII 
and pharmaceutically acceptable salts thereof, wherein
*, R1, g, R, X1, and d are as defined above for Formula VI;
B is a heterocyclene selected from the group consisting of: 
X is O, S, or Nxe2x80x94R3 wherein R3 is hydrogen or alkyl;
V is CH2;
E and Y are taken together with the phenylene to which they are attached to form a fused 9- or 10-membered bicyclic ring, containing from 0 to 3 heteroatoms in Exe2x80x94Y selected from N, O, and S, wherein E is a linker group containing 2 or 3 atoms of the bicyclic ring, and Y is a hydrogen bond donor group containing 1 atom of the bicyclic ring; and
one X1 is ortho to B and para to E.
More preferred are compounds of Formula VII and pharmaceutically acceptable salts thereof wherein
Y is selected from xe2x80x94N(H)xe2x80x94, xe2x80x94CH(OH)xe2x80x94, and xe2x80x94N(OH)xe2x80x94, and
E is selected from xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90Nxe2x80x94, xe2x80x94C(O)xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94C(O)xe2x80x94, xe2x80x94CH2xe2x80x94S(O)xe2x80x94, xe2x80x94CH2xe2x80x94S(O)2xe2x80x94, xe2x80x94Nxe2x95x90C(H)xe2x80x94, xe2x80x94N(H)xe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94Sxe2x80x94C(O)xe2x80x94, xe2x80x94Nxe2x95x90Nxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94C(H)xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94C(O)xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94S(O)xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94S(O)2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94C(O)xe2x80x94, xe2x80x94Nxe2x95x90CHxe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94C(O)xe2x80x94, xe2x80x94Sxe2x80x94CH2xe2x80x94C(O)xe2x80x94, and xe2x80x94N(H)xe2x80x94C(O)xe2x80x94C(O)xe2x80x94; or
Y is selected from xe2x95x90C(OH)xe2x80x94; and
E is selected from xe2x80x94CHxe2x95x90CHxe2x80x94C(H)xe2x95x90, xe2x80x94C(O)xe2x80x94C(H)xe2x95x90, xe2x80x94C(O)xe2x80x94Nxe2x95x90, xe2x80x94Oxe2x80x94Nxe2x95x90, xe2x80x94Sxe2x80x94Nxe2x95x90, xe2x80x94C(O)xe2x80x94N(H)xe2x80x94Nxe2x95x90, xe2x80x94CHxe2x95x90Nxe2x80x94Nxe2x95x90, xe2x80x94CHxe2x95x90N(O)xe2x80x94Nxe2x95x90, and xe2x80x94N(H)xe2x80x94C(O)xe2x80x94Nxe2x95x90.
Still more preferred are compounds of Formula VII and pharmaceutically acceptable salts thereof wherein
xe2x80x94Exe2x80x94Yxe2x80x94 is selected from the group consisting of
xe2x80x94CHxe2x95x90CHxe2x80x94N(H)xe2x80x94,
xe2x80x94(CH2)2xe2x80x94N(H)xe2x80x94,
xe2x80x94CHxe2x95x90Nxe2x80x94N(H)xe2x80x94,
xe2x80x94C(O)xe2x80x94CH2xe2x80x94N(H)xe2x80x94,
xe2x80x94CH2xe2x80x94C(O)xe2x80x94N(H)xe2x80x94,
xe2x80x94CH2xe2x80x94S(O)xe2x80x94N(H)xe2x80x94,
xe2x80x94CH2xe2x80x94S(O)2xe2x80x94N(H)xe2x80x94,
xe2x80x94CHxe2x95x90CHxe2x80x94CH(OH)xe2x80x94,
xe2x80x94(CH2)2xe2x80x94CH(OH)xe2x80x94,
xe2x80x94C(O)xe2x80x94C(H)xe2x95x90C(OH)xe2x80x94,
xe2x80x94C(O)xe2x80x94Nxe2x95x90C(OH)xe2x80x94,
xe2x80x94Nxe2x95x90CHxe2x80x94N(H)xe2x80x94,
xe2x80x94N(H)xe2x80x94C(O)xe2x80x94N(H)xe2x80x94,
xe2x80x94Oxe2x80x94C(O)xe2x80x94NHxe2x80x94,
xe2x80x94Sxe2x80x94C(O)xe2x80x94NHxe2x80x94,
xe2x80x94Oxe2x80x94Nxe2x95x90CH(OH)xe2x80x94,
xe2x80x94Sxe2x80x94Nxe2x95x90CH(OH)xe2x80x94,
xe2x80x94Nxe2x95x90Nxe2x80x94N(H)xe2x80x94,
xe2x80x94Nxe2x95x90Nxe2x80x94N(OH)xe2x80x94,
xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90C(OH)xe2x80x94,
xe2x80x94(CH2)3xe2x80x94CH(OH)xe2x80x94,
xe2x80x94(CH2)2xe2x80x94C(O)xe2x80x94N(H)xe2x80x94,
xe2x80x94(CH2)2xe2x80x94S(O)xe2x80x94N(H)xe2x80x94,
xe2x80x94(CH2)2xe2x80x94S(O)2xe2x80x94N(H)xe2x80x94,
xe2x80x94CHxe2x95x90CHxe2x80x94C(O)xe2x80x94N(H)xe2x80x94,
xe2x80x94C(O)xe2x80x94NHxe2x80x94Nxe2x95x90C(OH)xe2x80x94,
xe2x80x94CHxe2x95x90Nxe2x80x94Nxe2x95x90C(OH)xe2x80x94,
xe2x80x94CHxe2x95x90N(O)xe2x80x94Nxe2x95x90C(OH)xe2x80x94,
xe2x80x94N(H)xe2x80x94C(O)xe2x80x94Nxe2x95x90C(OH)xe2x80x94,
xe2x80x94Nxe2x95x90CHxe2x80x94C(O)xe2x80x94NHxe2x80x94,
xe2x80x94Oxe2x80x94CH2xe2x80x94C(O)xe2x80x94NHxe2x80x94,
xe2x80x94Sxe2x80x94CH2xe2x80x94C(O)xe2x80x94NHxe2x80x94, and
xe2x80x94N(H)xe2x80x94C(O)xe2x80x94C(O)xe2x80x94N(H)xe2x80x94.
Also preferred are compounds of Formula VIII 
and pharmaceutically acceptable salts thereof, wherein X1, d, *, R, V, R1, and g are as defined above for Formula VI, and X is O, S, or Nxe2x80x94R3 wherein R3 is hydrogen or alkyl.
More preferred is a compound of Formula VIII and a pharmaceutically acceptable salt thereof which is trans-6-{4-[methyl-(2-methyl-5-phenyl-furan-3-ylmethyl)-amino]-cyclohexyl}-3H-benzoxazol-2-one.
Also preferred are compounds of Formula IX 
and pharmaceutically acceptable salts thereof, wherein X1, d, *, R, V, R1, and g are as defined above for Formula VI, and X is O, S, or Nxe2x80x94R3 wherein R3 is hydrogen or alkyl.
More preferred is a compound of Formula IX and a pharmaceutically acceptable salt thereof, selected from the group consisting of:
trans-(R)-6-{4-[(2-oxo-3-phenyl-oxazolidin-5-ylmethyl)amino]-cyclohexyl}-3H-benzoxazol-2-one;
trans-(R)-6-{4-[methyl-(2-oxo-3-phenyl-oxazolidin-5-ylmethyl)amino]-cyclohexyl}-3H-benzoxazol-2-one.
Also preferred are compounds of Formula X 
and pharmaceutically acceptable salts thereof, wherein X1, d, R, V, R1, and g are as defined above for Formula VI, and X is O, S, or Nxe2x80x94R3 wherein R3 is hydrogen or alkyl.
More preferred is a compound of Formula X and a pharmaceutically acceptable salt thereof, selected from the group consisting of:
trans-6-{4-[(5-methyl-2-phenyl-thiazol-4-ylmethyl)-amino]-cyclohexyl}-3H-benzoxazol-2-one; and
trans-6-{4-(methyl-(5-methyl-2-phenyl-thiazol-4-ylmethyl)-amino]-cyclohexyl}-3H-benzoxazol-2-one.
Also preferred are compounds of Formula XI 
and pharmaceutically acceptable salts thereof, wherein X1, d, *, R, V, R1, and g are as defined above for Formula VI, and X is O, S, or Nxe2x80x94R3 wherein R3 is hydrogen or alkyl.
More preferred is a compound of Formula XI and a pharmaceutically acceptable salt thereof, selected from the group consisting of:
trans-6-(4-{[3-(4-fluoro-phenyl)-4,5-dihydro-isoxazol-5-ylmethyl]-amino}-cyclohexyl)-3H-benzoxazol-2-one; and
trans-6-(4-{[3-(4-fluoro-phenyl)-4,5-dihydro-isoxazol-5-ylmethyl]-methyl-amino}-cyclohexyl)-3H-benzoxazol-2-one.
Also preferred are compounds of Formula XII 
and pharmaceutically acceptable salts thereof, wherein X1, d, R, *, R1, g, V, and B are as defined above for Formula VI.
The invention also provides a pharmaceutical composition, comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent, carrier, or excipient.
In a preferred embodiment, the invention provides a pharmaceutical composition, comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
trans-6-(5-{[methyl-(4-phenyl-cyclohexyl)-amino]-methyl}-4,5-dihydro-isoxazol-3-yl)-3H-benzoxazol-2-one;
trans-6-{5-[4-(4-fluoro-phenyl)-cyclohexylamino]-methyl-2-oxo-oxazolidin-3-yl}-3H-benzoxazol-2-one; and
trans-6-(5-[{4-(4-fluoro-phenyl)-cyclohexyl]-methyl-amino}-methyl-2-oxo-oxazolidin-3-yl)-3H-benzoxazol-2-one;
together with a pharmaceutically acceptable diluent, carrier, or excipient.
The invention also provides a pharmaceutical composition, comprising a therapeutically effective amount of a compound of Formula VI, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent, carrier, or excipient.
In a preferred embodiment, the invention provides a pharmaceutical composition, comprising a therapeutically effective amount of a compound of Formula VI, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
trans-6-{4-[methyl-(2-methyl-5-phenyl-furan-3-ylmethyl)-amino]-cyclohexyl}-3H-benzoxazol-2-one;
trans-(R)-6-{4-[2-oxo-3-phenyl-oxazolidin-5-ylmethyl)-amino]-cyclohexyl}-3H-benzoxazol-2-one;
trans-(R)-6-{4-[methyl-(2-oxo-3-phenyl-oxazolidin-5-ylmethyl)-amino]-cyclohexyl}-3H-benzoxazol-2-one;
trans-6-{4-[(5-methyl-2-phenyl-thiazol-4-ylmethyl)-amino]-cyclohexyl}-3H-benzoxazol-2-one;
trans-6-{4-[methyl-(5-methyl-2-phenyl-thiazol-4-ylmethyl)-amino]-cyclohexyl}-3H-benzoxazol-2-one;
trans-6-(4-{[3-(4-fluoro-phenyl)-4,5-dihydro-isoxazol-5-ylmethyl]-amino}-cyclohexyl)-3H-benzoxazol-2-one; and
trans-6-(4-{[3-(4-fluoro-phenyl)-4,5-dihydro-isoxazol-5-ylmethyl]-methyl-amino}-cyclohexyl)-3H-benzoxazol-2-one;
together with a pharmaceutically acceptable diluent, carrier, or excipient.
The invention also provides a method of treating disorders responsive to the selective blockade of the N-methyl-D-aspartate receptor subtypes in a mammal, including a human, suffering therefrom, which comprises administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
In a preferred embodiment, the invention provides a method of treating disorders responsive to the selective blockade of the N-methyl-D-aspartate receptor subtypes in a mammal, including a human, suffering therefrom, comprising administering a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the disorder being treated is selected from stroke, cerebral ischemia, depression, trauma, hypoglycemia, anxiety, migraine headache, convulsions, aminoglycoside antibiotics-induced hearing loss, psychosis, glaucoma, CMV retinitis, opioid tolerance or withdrawal, pain, including chronic pain, neuropathic pain, or surgical pain, and urinary incontinence.
In a more preferred embodiment, the invention provides a method of treating disorders responsive to the selective blockade of the N-methyl-D-aspartate receptor subtypes in a mammal, including a human, suffering therefrom comprising administering a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the disorder being treated is pain.
In another more preferred embodiment, the invention provides a method of treating disorders responsive to the selective blockade of the N-methyl-D-aspartate receptor subtypes in a mammal, including a human, suffering therefrom comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the disorder being treated is Parkinson""s disease.
In a still more preferred embodiment, the invention provides a method of treating disorders responsive to the selective blockade of the N-methyl-D-aspartate receptor subtypes in a mammal, including a human, suffering therefrom comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
trans-6-(5-{[methyl-(4-phenyl-cyclohexyl)-amino]-methyl}-4,5-dihydro-isoxazol-3-yl)-3H-benzoxazol-2-one;
trans-6-{5-[4-(4-fluoro-phenyl)-cyclohexylamino]-methyl-2-oxo-oxazolidin-3-yl}-3H-benzoxazol-2-one; and
trans-6-(5-{[4-(4-fluoro-phenyl)-cyclohexyl]-methyl-amino}-methyl-2-oxo-oxazolidin-3-yl)-3H-benzoxazol-2-one;
together with a pharmaceutically acceptable diluent, carrier, or excipient.
In another more preferred embodiment, the invention provides a method of treating disorders responsive to the selective blockade of the N-methyl-D-aspartate receptor subtypes in a mammal, including a human, suffering therefrom comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof, further comprising administering a dopamine agonist.
In another more preferred embodiment, the invention provides a method of treating disorders responsive to the selective blockade of the N-methyl-D-aspartate receptor subtypes in a mammal, including a human, suffering therefrom comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof, further comprising administering a dopamine agonist wherein said dopamine agonist is L-DOPA.
In another preferred embodiment, the invention provides a method of treating disorders comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof in unit dosage form.
The invention also provides a method of treating disorders responsive to the selective blockade of the N-methyl-D-aspartate receptor subtypes in a mammal, including a human, suffering therefrom which comprises administering a compound of Formula VI or a pharmaceutically acceptable salt thereof.
In a preferred embodiment, the invention provides a method of treating disorders responsive to the selective blockade of the N-methyl-D-aspartate receptor subtypes in a mammal, including a human, suffering therefrom comprising administering a compound of Formula VI or a pharmaceutically acceptable salt thereof, wherein the disorder being treated is selected from stroke, cerebral ischemia, depression, trauma, hypoglycemia, anxiety, migraine headache, convulsions, aminoglycoside antibiotics-induced hearing loss, psychosis, glaucoma, CMV retinitis, opioid tolerance or withdrawal, pain, including chronic pain, neuropathic pain, or surgical pain, and urinary incontinence.
In a more preferred embodiment, the invention provides a method of treating disorders responsive to the selective blockade of the N-methyl-D-aspartate receptor subtypes in a mammal, including a human, suffering therefrom comprising administering a compound of Formula VI or a pharmaceutically acceptable salt thereof, wherein the disorder being treated is pain.
In another more preferred embodiment, the invention provides a method of treating disorders responsive to the selective blockade of the N-methyl-D-aspartate receptor subtypes in a mammal, including a human, suffering therefrom comprising administering a compound of Formula VI or a pharmaceutically acceptable salt thereof, wherein the disorder being treated is Parkinson""s disease.
In a still more preferred embodiment, the invention provides a method of treating disorders responsive to the selective blockade of the N-methyl-D-aspartate receptor subtypes in a mammal, including a human, suffering therefrom comprising administering a compound of Formula VI or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
trans-6-{4-[methyl-(2-methyl-5-phenyl-furan-3-ylmethyl)-amino]-cyclohexyl}-3H-benzoxazol-2-one;
trans-(R)-6-{4-[2-oxo-3-phenyl-oxazolidin-5-ylmethyl)-amino]-cyclohexyl}-3H-benzoxazol-2-one;
trans-(R)-6-{4-[methyl-(2-oxo-3-phenyl-oxazolidin-5-ylmethyl)-amino]-cyclohexyl}-3H-benzoxazol-2-one;
trans-6-{4-[(5-methyl-2-phenyl-thiazol-4-ylmethyl)-amino]-cyclohexyl}-3H-benzoxazol-2-one;
trans-6-{4-[methyl-(5-methyl-2-phenyl-thiazol-4-ylmethyl)-amino]-cyclohexyl}-3H-benzoxazol-2-one;
trans-6-(4-{[3-(4-fluoro-phenyl)-4,5-dihydro-isoxazol-5-ylmethyl]-amino}-cyclohexyl)-3H-benzoxazol-2-one; and
trans-6-(4-{[3-(4-fluoro-phenyl)-4,5-dihydro-isoxazol-5-ylmethyl]-methyl-amino}-cyclohexyl)-3H-benzoxazol-2-one;
together with a pharmaceutically acceptable diluent, carrier, or excipient.
In another more preferred embodiment, the invention provides a method of treating disorders responsive to the selective blockade of the N-methyl-D-aspartate receptor subtypes in a mammal, including a human, suffering therefrom comprising administering a compound of Formula VI or a pharmaceutically acceptable salt thereof, further comprising administering a dopamine agonist.
In another more preferred embodiment, the invention provides a method of treating disorders responsive to the selective blockade of the N-methyl-D-aspartate receptor subtypes in a mammal, including a human, suffering therefrom comprising administering a compound of Formula VI or a pharmaceutically acceptable salt thereof, further comprising administering a dopamine agonist wherein said dopamine agonist is L-DOPA.
In another preferred embodiment, the invention provides a method of treating disorders comprising administering a compound of Formula VI or a pharmaceutically acceptable salt thereof in unit dosage form.
Another embodiment of the present invention is a compound selected from the group consisting of:
6-(cyclohexanone-4-yl)benzoxazolin-2-one;
3-(3-benzyloxy-4-nitro-phenyl)-5-[methyl-(4-phenyl-cyclohexyl)-amino]methyl-4,5-dihydro-isoxazole;
3-(4-amino-3-hydroxy-phenyl)-5-[methyl-(4-phenyl-cyclohexyl)-amino]methyl-4,5-dihydro-isoxazole;
3-(methylamino)methyl-2-methyl-5-phenyl-furan;
5-(aminomethyl)-3-phenyl-2-oxo-oxazolidine;
6-[5-(aminomethyl)-2-oxo-oxazolidin-3-yl]-3H-benzoxazol-2-one;
4-(aminomethyl)-5-methyl-2-phenyl-thiazole; and
5-(aminomethyl)-3-(4-fluorophenyl)-4,5-dihydro-isoxazole.
Another embodiment of the present invention is a method of preparing compounds of Formula I 
and pharmaceutically acceptable salts thereof, wherein V is (CH2)n wherein n is an integer of from 1 to 4 and R1, g, *, R, B, X1, d, E, and Y are as defined above for Formula I, comprising reductively aminating a ketone of Formula XIII 
wherein R1 and g are as defined above, with an amine of Formula XIV 
wherein R, V, B, X1, d, E, and Y are as defined above.
Another embodiment of the present invention is a method of preparing a compound of Formula VI 
and pharmaceutically acceptable salts thereof wherein V is (CH2)n wherein n is an integer of from 1 to 4 and Y, E, X1, d, R, B, *, R1, and g are as defined above for Formula VI, comprising reductively aminating a ketone of Formula XV 
wherein Y, E, X1, and d are as defined above, with an amine of Formula XVI 
wherein R, V, B, R1, and g are as defined above.